When the project was initiated in the early 70's, the objective had been to determine the three- dimensional atomic resolution structure of a virus - any virus. With the attainment of this goal some 8 years later, attention shifted from plant viruses to the greater challenge of animal viruses. The first success came in 1985 with the work on human rhinovirus serotype 14. The associated technological developments provided the momentum for structural studies of a large variety of animal, plant, and bacterial viruses. The focus of these projects was the interaction of viruses with cellular factors (such as receptors and neutralizing antibodies), the conformational changes that occur during cell entry, and the assembly of the virus from its constituent parts. Since writing the previous competitive renewal ten years ago, major advances have been made in the use of cryo-electron microcopy and image reconstruction techniques for structural studies of uncrystallizable viral assemblies in combination with crystallographic investigations of smaller viral components. It has become possible to obtain "pseudo-atomic resolution" structures of enormous viruses with diameters ranging from 1,000 to 7,500 A and with genomes that provide the potential for most of the function of a biological cell. Many of these giant viruses retain accurate icosahedral symmetry, both of their capsid and often of their internal lipid envelope, providing a handle for the investigation of particles that approach the size and complexity of a small bacterium. We plan to study three groups of large, icosahedral, dsDNA viruses: (i) the algal Paramecium bursaria Chlorella virus-1 (PBCV-1), (ii) the insect Chilo iridescent virus (CIV), and (iii) the amoeba Mimivirus. We plan to use X-ray crystallography to study their major and many minor coat proteins, their cell attachment proteins, and their unique enzymes that glycosylate the viral surface proteins. Combining the structural techniques with virological investigations should extend information on how these viruses assemble and infect their hosts. At the same time, the earlier work on small icosahedral (ssRNA) picorna- and (ssDNA) parvoviruses is to continue, Picornaviruses will be examined that require not only a principal cell surface receptor molecule for recognition and cell entry, but their efficiency of infection may be dependent on accessory receptors. In contrast to picornaviruses, we plan to follow up on the initial indications that specific cellular receptors might cause cooperative conformational changes on the surface of parvoviruses, severely limiting the number of receptors that can bind or are needed for infection. The human B19 parvovirus and other mammalian parvoviruses will be examined for their interactions with neutralizing antibodies.